RESUMEN
Background: Colchicine is a common therapeutic agent for inflammatory conditions such as gout, yet its narrow therapeutic range frequently results in cases of overdose and subsequent poisoning. Acute colchicine poisoning can be difficult to identify due to its nonspecific clinical manifestations, posing a diagnostic challenge for emergency physicians without a clear history of colchicine ingestion. Case presentation: This report describes a tragic case of acute colchicine poisoning that resulted in three familial homicides. The patients presented with fever, abdominal pain, and diarrhea, which rapidly escalated to shock during their emergency department visits. Laboratory tests revealed a marked leukocytosis, mild elevation in procalcitonin (PCT), significantly elevated creatine kinase (CK) and CK-MB levels, and liver function abnormalities. Despite treatment with carbapenem antibiotics and aggressive fluid resuscitation, the patients' condition deteriorated, marked by a progressive decline in leukocytes and neutrophils. Initially misdiagnosed as septic shock, the ineffectiveness of the standard treatment protocols led to a fatal outcome for all three individuals. Conclusion: Emergency physicians should consider acute colchicine poisoning as a differential diagnosis in patients presenting with shock and the following clinical indicators: (1) pronounced increase in peripheral leukocytes with a disproportionate rise in neutrophils; (2) discordance between the level of serum procalcitonin and the severity of presumed septic shock; (3) early increase in serum creatine kinase (CK) and CK-MB; (4) poor response to antibiotics and resuscitative efforts, accompanied by a continuous decrease in white blood cells and neutrophils. This case underscores the critical need for awareness of colchicine toxicity in the emergency setting, particularly when the clinical presentation mimics septic shock but fails to respond to standard treatments.
RESUMEN
Sepsis is a severe systemic infectious disease that often leads to multi-organ dysfunction. One of the common and serious complications of sepsis is renal injury. In this study, we aimed to investigate the potential mechanistic role of a novel compound called H-151 in septic kidney injury. We also examined its impact on renal function and mouse survival rates. Initially, we confirmed abnormal activation of the STING-TBK1 signaling pathway in the kidneys of septic mice. Subsequently, we treated the mice with H-151 and observed significant improvement in sepsis-induced renal dysfunction. This was evidenced by reductions in blood creatinine and urea nitrogen levels, as well as a marked decrease in inflammatory cytokine levels. Furthermore, H-151 substantially improved the seven-day survival rate of septic mice, indicating its therapeutic potential. Importantly, H-151 also exhibited an inhibitory effect on renal apoptosis levels, further highlighting its mechanism of protecting against septic kidney injury. These study findings not only offer new insights into the treatment of septic renal injury but also provide crucial clues for further investigations into the regulatory mechanisms of the STING-TBK1 signaling pathway and potential drug targets.
Asunto(s)
Lesión Renal Aguda , Modelos Animales de Enfermedad , Lipopolisacáridos , Proteínas de la Membrana , Proteínas Serina-Treonina Quinasas , Sepsis , Transducción de Señal , Animales , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/prevención & control , Lesión Renal Aguda/tratamiento farmacológico , Ratones , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas de la Membrana/metabolismo , Sepsis/complicaciones , Sepsis/metabolismo , Sepsis/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Masculino , Riñón/patología , Riñón/metabolismo , Riñón/efectos de los fármacos , Apoptosis/efectos de los fármacos , Ratones Endogámicos C57BL , Citocinas/metabolismoRESUMEN
OBJECTIVE: Do-not-attempt-resuscitation (DNAR) orders are designed to allow patients to opt out of receiving cardiopulmonary resuscitation in the event of a cardiac arrest. While DNAR has become a standard component of medical care, there is limited research available specifically focusing on DNAR orders in the context of emergency departments in China. This study aimed to fill that gap by examining the factors related to DNAR orders among patients in the emergency department of a general tertiary teaching hospital in China. DESIGN: Retrospective observational study. SETTING: Emergency department. PARTICIPANTS: This study and analysis on adult patients with DNAR or no DNAR data between 1 January 2022 and 1 January 2023 in the emergency department of a large academic comprehensive tertiary teaching hospital. A total of 689 were included in our study. PRIMARY OUTCOME MEASURES: Whether the patient received DNAR was our dependent variable. RESULTS: Among the total patients, 365 individuals (53.0%) had DNAR orders. The following variables, including age, sex, age-adjusted Charlson comorbidity index (ACCI), primary diagnosis of cardiogenic or cancer related, history of neurological dysfunction or cancer, were independently associated with the difference between the DNAR group and the no DNAR group. Furthermore, there were significant statistical differences observed in the choice of DNAR among patients with different stages of cancer. CONCLUSIONS: In comparison to the no DNAR group, patients with DNAR were characterised by being older, having a higher proportion of female patients, higher ACCI scores, a lower number of patients with a primary diagnosis of cardiogenic and a higher number of patients with a primary diagnosis of cancer related, history of neurological dysfunction or cancer.
Asunto(s)
Servicio de Urgencia en Hospital , Neoplasias , Humanos , Adulto , Femenino , Órdenes de Resucitación , Estudios Retrospectivos , Hospitales de EnseñanzaRESUMEN
BACKGROUND Severe hypokalemia, which often causes life-threatening malignant arrhythmias, is usually first diagnosed in the Emergency Department (ED). It is important to note that hypokalemia is often closely and complexly related to renal tubular acidosis (RTA) associated with autoimmune diseases such as Sjögren's syndrome (SS), especially in females with acute myopathy or acute liver injury (ALI). Severe hypokalemia can directly cause muscle injury, which can lead to hyper-creatine kinaseemia (HCK) and ALI, while SS can also directly cause hypokalemia, HCK, and even ALI and renal tubular/interstitial injury. Therefore, by reporting a rare case of SS-associated RTA (SS-RTA), we systematically reviewed the relationship between SS-RTA and severe hypokalemia, which may be beneficial to increase attention on this topic. CASE REPORT A 35-year-old female patient who presented to the ED primarily for limb weakness symptoms was initially diagnosed with severe hypokalemia, acute myopathy, and ALI. She was eventually diagnosed with primary SS (pSS) and SS-RTA, although she did not present with the typical dry mouth, dry eyes, and other clinical manifestations of SS. CONCLUSIONS Severe hypokalemia is a serious life-threatening emergency, and although the differential diagnosis is very broad, we should be aware of RTA associated with autoimmune diseases such as SS in female patients, especially when combined with clinical manifestations such as acute myopathy and ALI that cannot be explained by other causes. Simultaneously, we hope to be able to guide emergency physicians encountering similar patients to complete the diagnostic and therapeutic process.
Asunto(s)
Acidosis Tubular Renal , Enfermedades Autoinmunes , Hipopotasemia , Enfermedades Musculares , Síndrome de Sjögren , Humanos , Femenino , Adulto , Acidosis Tubular Renal/complicaciones , Acidosis Tubular Renal/diagnóstico , Síndrome de Sjögren/complicaciones , Síndrome de Sjögren/diagnóstico , Hipopotasemia/etiología , CreatinaRESUMEN
BACKGROUND: There is no available viable treatment for Sepsis-Induced Cardiomyopathy (SIC), a common sepsis complication with a higher fatality risk. The septic patients showed an abnormal activation of the renin angiotensin (Ang) aldosterone system (RAAS). However, it is not known how the Ang II and Ang-(1-7) affect SIC. METHODS: Peripheral plasma was collected from the Healthy Control (HC) and septic patients and Ang II and Ang-(1-7) protein concentrations were measured. The in vitro and in vivo models of SIC were developed using Lipopolysaccharide (LPS) to preliminarily explore the relationship between the SIC state, Ang II, and Ang-(1-7) levels, along with the protective function of exogenous Ang-(1-7) on SIC. RESULTS: Peripheral plasma Ang II and the Ang II/Ang-(1-7) levels in SIC-affected patients were elevated compared to the levels in HC and non-SIC patients, however, the HC showed higher Ang-(1-7) levels. Furthermore, peripheral plasma Ang II, Ang II/Ang-(1-7), and Ang-(1-7) levels in SIC patients were significantly correlated with the degree of myocardial injury. Additionally, exogenous Ang-(1-7) can attenuate inflammatory response, reduce oxidative stress, maintain mitochondrial dynamics homeostasis, and alleviate mitochondrial structural and functional damage by inhibiting nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, thus alleviating SIC. CONCLUSIONS: Plasma Ang-(1-7), Ang II, and Ang II/Ang-(1-7) levels were regarded as significant SIC biomarkers. In SIC, therapeutic targeting of RAAS, for example with Ang-(1-7), may exert protective roles against myocardial damage.
Asunto(s)
Cardiomiopatías , Sepsis , Humanos , FN-kappa B/metabolismo , Proteínas Quinasas Activadas por Mitógenos , Células Cultivadas , Angiotensina II/metabolismo , Cardiomiopatías/tratamiento farmacológico , Cardiomiopatías/etiología , Sepsis/complicaciones , Sepsis/tratamiento farmacológicoRESUMEN
OBJECTIVES: Sepsis can cause myocardial injury, which is one of the leading causes of death in critically ill patients. Fish oil rich in omega-3 polyunsaturated fatty acids (PUFAs) in ultralong chains has immunomodulatory effects and can inhibit the production of various critically ill proinflammatory cytokines. Therefore, this study focused on whether ω-3 PUFAs have a protective effect on sepsis-induced cardiomyopathy (SIC). METHODS: Male 6-8 weeks old C57BL/6 mice were pretreated with 3% special fish oil supplement rat food for seven consecutive days prior to surgery. Cecal ligation and puncture (CLP) was perfromed to induce polymicrobial sepsis.The cardiac function was assessed by echocardiography, apoptosis of cardiomyocyte were detected by TUNEL assay and Western blotting, and the level of TNF-α, IL-6, and IL-1ß in plasma was determined 24h after CLP. RESULTS: Pretreatment with omega-3 PUFAs attenuated cardiomyocyte apoptosis, decreased the production of proinflammatory cytokines, attenuated the SIC, and improved the survival rate of septic mice induced by CLP. CONCLUSIONS: ω-3 PUFAs alleviate SIC through attenuating cardiomyocyte apoptosis, which provides a new direction for the prevention and treatment of SIC.
Asunto(s)
Apoptosis , Cardiomiopatías , Ácidos Grasos Omega-3 , Miocitos Cardíacos , Animales , Masculino , Ratones , Apoptosis/efectos de los fármacos , Cardiomiopatías/tratamiento farmacológico , Enfermedad Crítica , Citocinas , Ácidos Grasos Omega-3/farmacología , Ácidos Grasos Omega-3/uso terapéutico , Aceites de Pescado/farmacología , Aceites de Pescado/uso terapéutico , Ratones Endogámicos C57BL , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Sepsis/complicacionesRESUMEN
BACKGROUND: Blue rubber bleb nevus syndrome is a rare vascular malformation syndrome with unclear etiopathogenesis and noncurative treatments. It is characterized by multiple vascular malformations of the skin, gastrointestinal tract, and other visceral organs. The most common symptoms are intermittent gastrointestinal bleeding and secondary iron deficiency anemia, thus requiring repeated blood transfusions and hospitalizations. It is easily missed and misdiagnosed, and there is no specific treatment. CASE SUMMARY: We report a case of blue rubber bleb nevus syndrome combined with disseminated intravascular coagulation and efficacy of treatment with argon plasma coagulation under enteroscopy and sirolimus. A 56-year-old female patient was admitted to the hospital with 3-year history of fatigue and dizziness that had aggravated over the past 10 d with melena. The patient had a history of repeated melena and multiple venous hemangiomas from childhood. After treatment with argon plasma coagulation combined with sirolimus for nearly 8 wk, the patient's serum hemoglobin increased to 100 g/L. At the 12-mo follow-up, the patient was well with stable hemoglobin (102 g/L) and no recurrent intestinal bleeding. CONCLUSION: Argon plasma coagulation and sirolimus may be an efficacious and safe treatment for blue rubber bleb nevus syndrome, which currently has no recommended treatments.
RESUMEN
Sepsis-induced cardiomyopathy (SIC) is a serious complication of sepsis with high mortality but no effective treatment. The renin angiotensin (Ang) aldosterone system (RAAS) is activated in patients with sepsis but it is unclear how the Ang II/Ang II type 1 receptor (AT1R) axis contributes to SIC. This study examined the link between the Ang II/AT1R axis and SIC as well as the protective effect of AT1R blockers (ARBs). The Ang II level in peripheral plasma and AT1R expression on monocytes were significantly higher in patients with SIC compared with those in non-SIC patients and healthy controls and were correlated with the degree of myocardial injury. The ARB losartan reduced the infiltration of neutrophils, monocytes, and macrophages into the heart and spleen of SIC mice. Additionally, losartan regulated macrophage polarization from the M1 to the M2 subtype via nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, thereby maintaining the mitochondrial dynamics balance in cardiomyocytes and reducing oxidative stress and cardiomyocyte apoptosis. In conclusion, the plasma Ang II level and AT1R expression on plasma monocytes are an important biomarker in SIC. Therapeutic targeting of AT1R, for example with losartan, can potentially protect against myocardial injury in SIC.
Asunto(s)
Cardiomiopatías , Sepsis , Ratones , Animales , Losartán/farmacología , Losartán/uso terapéutico , FN-kappa B/metabolismo , Antagonistas de Receptores de Angiotensina , Receptor Toll-Like 4 , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Proteínas Quinasas Activadas por Mitógenos , Inhibidores de la Enzima Convertidora de Angiotensina , Receptor de Angiotensina Tipo 1/metabolismo , Angiotensina II/farmacología , Sepsis/complicaciones , Sepsis/tratamiento farmacológico , Cardiomiopatías/tratamiento farmacológico , Cardiomiopatías/etiología , Macrófagos/metabolismoRESUMEN
Objective: To evaluate the diagnostic performance of metagenomic next-generation sequencing (mNGS) and culture in pathogen detection among intensive care unit (ICU) and non-ICU patients with suspected pulmonary infection. Methods: In this prospective study, sputum samples were collected from patients with suspected pulmonary infection for 2 consecutive days and then subjected to DNA or RNA sequencing by mNGS or culture; 62 ICU patients and 60 non-ICU patients were admitted. In the end, comparisons were made on the pathogen species identified by mNGS and culture, the overall performance of these two methods in pathogen detection, and the most common pathogens detected by mNGS between the ICU and non-ICU groups. Results: In DNA and RNA sequencing, the positive rate of pathogen detection reached 96.69% (117/121) and 96.43% (108/112), respectively. In culture tests, the positive rate of the pathogen was 39.34% (48/122), much lower than that of DNA and RNA sequencing. In general, the positive rate of pathogen detection by sputum mNGS was significantly higher than that of sputum culture in the total and non-ICU groups (p < 0.001) but did not show a significant difference when compared to the result of sputum culture in the ICU group (p = 0.08). Haemophilus spp., Candida albicans, Enterococcus spp., and viruses from the mNGS results were excluded before comparing the overall performance of these two methods in pathogen detection. Specifically, among the 10 most common bacteria implied from the mNGS results, significant differences were observed in the number of cases of Haemophilus parainfluenzae, Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Staphylococcus aureus, and Enterococcus faecalis between the ICU and non-ICU groups (p < 0.05). Conclusions: This study demonstrated the superiority of mNGS over culture in detecting all kinds of pathogen species in sputum samples. These results indicate that mNGS may serve as a valuable tool to identify pathogens, especially for ICU patients who are more susceptible to mixed infections.
Asunto(s)
Metagenómica , Neumonía , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Metagenoma , Metagenómica/métodos , Neumonía/microbiología , Estudios Prospectivos , Sensibilidad y EspecificidadRESUMEN
Acute kidney injury (AKI) is a clinical syndrome in which kidney function declines sharply due to various reasons. Although the morbidity and mortality of AKI are high, the mechanism of occurrence and development of AKI has not been fully elucidated, and precise prevention and treatment measures are lacking. Epigenetics is a branch of genetics that provides a new perspective to explore the pathophysiology of AKI and renal repair. A large amount of literature shows that the methylation mechanism of H3 in histones is closely related to the development of kidney diseases. The sorting out of histone H3 methylation mechanism in AKI and kidney repair can help understand the pathophysiological process of the disease more deeply. It may also provide new ideas for diagnosing and treating of the disease.
Asunto(s)
Lesión Renal Aguda , Histonas , Lesión Renal Aguda/genética , Lesión Renal Aguda/metabolismo , Epigénesis Genética , Histonas/metabolismo , Humanos , Riñón/metabolismo , Metilación , Procesamiento Proteico-PostraduccionalRESUMEN
BACKGROUND: Sepsis, a life-threatening organ dysfunction induced by infection, is a major public health problem. This study aimed to evaluate the frequency and mortality of sepsis, severe sepsis, and septic shock in China. METHODS: We Searched MEDLINE, Embase, PubMed, and Cochrane Library from 1 January 1992 to 1 June 2020 for studies that reported on the frequency and mortality of sepsis, severe sepsis, and septic shock conducted in China. Random effects models were performed to estimate the pooled frequency and mortality of sepsis, severe sepsis, and septic shock. RESULTS: Our search yielded 846 results, of which 29 studies were included in this review. The pooled frequency of sepsis was estimated at 33.6% (95% CI 25.9% to 41.3%, I2 = 99.2%; p < 0.001), and the pooled mortality of sepsis, severe sepsis and septic shock were 29.0% (95% CI 25.3%-32.8%, I2 = 92.1%; p = 0), 31.1% (95% CI 25.3% to 36.9%, I2 = 85.8%; p < 0.001) and 37.3% (95% CI 28.6%-46.0%, I2 = 93.5%; p < 0.001). There was significant heterogeneity between studies. With a small number of included studies and the changing definition of sepsis, trends in sepsis frequency and mortality were not sufficient for analysis. Epidemiological data on sepsis in the emergency department (ED) are severely lacking, and more research is urgently needed in this area is urgently needed. CONCLUSIONS: Our findings indicated that the frequency and mortality of sepsis and septic shock in China were much higher than North America and Europe countries. Based on our results, an extremely high incidence and mortality of sepsis and septic shock in China's mainland requires more healthcare budget support. Epidemiological data on sepsis and septic shock in ED are severely lacking, and more research is urgently needed in this area. Trial registration This systematic review was conducted according to the statement of the preferred reporting items for systematic review (PROSPERO CRD42021243325) and the meta-analysis protocols (PRISMA-P).
Asunto(s)
Sepsis , Choque Séptico , Humanos , China/epidemiología , Sepsis/epidemiología , Choque Séptico/epidemiologíaRESUMEN
Acute myocardial infarction (AMI) is one of the leading causes of death globally, with a mortality rate of over 20%. However, the diagnostic biomarkers frequently used in current clinical practice have limitations in both sensitivity and specificity, likely resulting in delayed diagnosis. This study aimed to identify potential diagnostic biomarkers for AMI and explored the possible mechanisms involved. Datasets were retrieved from the Gene Expression Omnibus. First, we identified differentially expressed genes (DEGs) and preserved modules, from which we identified candidate genes by LASSO (least absolute shrinkage and selection operator) regression and the SVM-RFE (support vector machine-recursive feature elimination) algorithm. Subsequently, we used ROC (receiver operating characteristic) analysis to evaluate the diagnostic accuracy of the candidate genes. Thereafter, functional enrichment analysis and an analysis of immune infiltration were implemented. Finally, we assessed the association between biomarkers and biological processes, infiltrated cells, clinical traits, tissues and time points. We identified nine preserved modules containing 1,016 DEGs and managed to construct a diagnostic model with high accuracy (GSE48060: AUC = 0.923; GSE66360: AUC = 0.973) incorporating two genes named S100A9 and SOCS3. Functional analysis revealed the pivotal role of inflammation; immune infiltration analysis indicated that eight cell types (monocytes, epithelial cells, neutrophils, CD8+ T cells, Th2 cells, NK cells, NKT cells and platelets) were likely involved in AMI. Furthermore, we observed that S100A9 and SOCS3 were correlated with inflammation, variably infiltrated cells, clinical traits of patients, sampling tissues and sampling time points. In conclusion, we suggested S100A9 and SOCS3 as diagnostic biomarkers of AMI and discovered their association with inflammation, infiltrated immune cells and other factors.
Asunto(s)
Calgranulina B , Perfilación de la Expresión Génica , Infarto del Miocardio , Proteína 3 Supresora de la Señalización de Citocinas , Biomarcadores , Calgranulina B/genética , Perfilación de la Expresión Génica/métodos , Regulación de la Expresión Génica , Humanos , Inflamación , Infarto del Miocardio/diagnóstico , Infarto del Miocardio/genética , Proteína 3 Supresora de la Señalización de Citocinas/genéticaRESUMEN
Rutin is a flavanol-type polyphenol that consists of flavanol quercetin and the disaccharide rutinose, which has been reported to exert various biological effects such as antioxidant and anti-inflammatory activities. It is not clear whether rutin has a protective effect on sepsis-induced cardiomyopathy (SIC). In this study, we used male C57BL/6 mice and cecal ligation and puncture (CLP) surgery to establish the model of SIC. Rutin was precautionarily treated (50, 100, 200 mg/kg per day, 7 days) before CLP. The results showed that rutin pretreatment (100, 200 mg/kg per day, 7 days) reduced the mortality of murine sepsis. We chose the 100 mg/kg dose for further studies. Mice were pretreatment with rutin (100 mg/kg per day, 7 days) before subjected to CLP, and myocardial tissue and blood samples were collected 24 h after CLP. Serum levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and cTNT decreased, while interleukin-10 (IL-10) increased with rutin pretreatment. The cardiomyocytes apoptosis and mitochondrial dysfunction were also alleviated with rutin pretreatment. In conclusion, this study confirmed the efficacy of rutin-enriched diet in the prophylaxis of cardiac apoptosis and cardiac injury induced by CLP in mouse model. It provides a potential new approach on SIC prophylaxis in sepsis.
RESUMEN
Sepsis-associated encephalopathy (SAE) is a diffuse central nervous system (CNS) dysfunction during sepsis, and is associated with increased mortality and poor outcomes in septic patients. Despite the high incidence and clinical relevance, the exact mechanisms driving SAE pathogenesis are not yet fully understood, and no specific therapeutic strategies are available. Regulatory T cells (Tregs) have a role in SAE pathogenesis, thought to be related with alleviation of sepsis-induced hyper-inflammation and immune responses, promotion of T helper (Th) 2 cells functional shift, neuroinflammation resolution, improvement of the blood-brain barrier (BBB) function, among others. Moreover, in a clinical point of view, these cells have the potential value of improving neurological and psychiatric/mental symptoms in SAE patients. This review aims to provide a general overview of SAE from its initial clinical presentation to long-term cognitive impairment and summarizes the main features of its pathogenesis. Additionally, a detailed overview on the main mechanisms by which Tregs may impact SAE pathogenesis is given. Finally, and considering that Tregs may be a novel target for immunomodulatory intervention in SAE, different therapeutic options, aiming to boost peripheral and brain infiltration of Tregs, are discussed.
RESUMEN
Sepsis is a syndrome characterized by life-threatening organ dysfunction caused by the dysregulated host response to an infection. Sepsis, especially septic shock and multiple organ dysfunction is a medical emergency associated with high morbidity, high mortality, and prolonged after-effects. Over the past 20 years, regulatory T cells (Tregs) have been a key topic of focus in all stages of sepsis research. Tregs play a controversial role in sepsis based on their heterogeneous characteristics, complex organ/tissue-specific patterns in the host, the multi-dimensional heterogeneous syndrome of sepsis, the different types of pathogenic microbiology, and even different types of laboratory research models and clinical research methods. In the context of sepsis, Tregs may be considered both angels and demons. We propose that the symptoms and signs of sepsis can be attenuated by regulating Tregs. This review summarizes the controversial roles and Treg checkpoints in sepsis.
Asunto(s)
Sepsis , Choque Séptico , Humanos , Sepsis/complicaciones , Choque Séptico/diagnóstico , Linfocitos T Reguladores/patologíaRESUMEN
Sepsis is a life-threatening syndrome with a high incidence and a weighty economic burden. The cytokines storm in the early stage and the state of immunosuppression in the late stage contribute to the mortality of sepsis. Immune checkpoints expressed on lymphocytes and APCs, including CD28, CTLA-4, CD80, CD86, PD-1 and PD-L1, CD40 and CD40L, OX40 and OX40L, 4-1BB and 4-1BBL, BTLA, TIM family, play significant roles in the pathogenesis of sepsis through regulating the immune disorder. The specific therapies targeting immune checkpoints exhibit great potentials in the animal and preclinical studies, and further clinical trials are planning to implement. Here, we review the current literature on the roles played by immune checkpoints in the pathogenesis and treatment of sepsis. We hope to provide further insights into this novel immunomodulatory strategy.
Asunto(s)
Antígeno B7-1 , Sepsis , Animales , Antígenos CD28 , Humanos , Tolerancia Inmunológica , Inmunomodulación , Sepsis/terapiaRESUMEN
Decreased serum thyroid hormone levels and their prediction of mortality in septic patients are still controversial, especially with the evolution of the definition of sepsis. This study aimed to assess the ability of thyroid hormone disorders to predict the early mortality of patients with septic shock defined by Sepsis-3. Sixty-three adult patients with septic shock admitted to a university hospital emergency intensive care unit (EICU) were studied. Serum free T3 (FT3), free T4 (FT4), thyroid stimulating hormone (TSH), C-reactive protein (CRP), procalcitonin (PCT), and lactate levels were determined and compared with survival status and organ dysfunction. Among the 63 patients studied, lower serum FT3 and FT4 levels were significantly associated with higher sequential organ failure assessment (SOFA) scores. Patients with septic shock with lower levels of FT3 (≤ 1.70 pmol/L) and FT4 (≤ 9.99 pmol/L) had significantly increased 28-day mortality. There was no significant difference in the serum TSH level between the survivor and nonsurvivor groups. The areas under the receiver operating characteristic curves for FT3 and FT4 levels were associated with 28-day mortality (0.92 and 0.89, respectively) and were higher than that for SOFA (0.82), CRP (0.65) and lactate (0.59). The decrease in serum levels of FT3 and FT4 in patients with septic shock is associated with the severity of organ dysfunction and 28-day mortality. Early detection of serum FT3 and FT4 levels could help clinicians to identify patients at high risk of clinical deterioration.
Asunto(s)
Choque Séptico/sangre , Choque Séptico/mortalidad , Hormonas Tiroideas/sangre , China/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Puntuaciones en la Disfunción de Órganos , Valor Predictivo de las Pruebas , Estudios Prospectivos , Pruebas de Función de la TiroidesRESUMEN
Neuropilin-1 (Nrp-1) contributes to maintaining the stability of CD4+ CD25+ regulatory T cells (Tregs). We investigated the impact of Nrp-1 on the stability of CD4+ CD25+ Tregs, and the underlying signaling pathways, in a model of sepsis. Splenic CD4+ CD25+ Tregs were either treated with anti-Nrp-1, transfected to silence Nrp-1 and inhibitor of NF-κB kinase subunit beta (IKKß), or administered ammonium pyrrolidine dithiocarbamate (PDTC), followed by recombinant semaphorin 3A (rSema3A), in a simulation of sepsis. After the creation of a sepsis model in mice, anti-Nrp-1 was administered. The expression of the gene encoding forkhead box protein P-3 foxp3-Treg-specific demethylated region (foxp3-TSDR), the apoptosis rate, the expression of Foxp-3, cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), and transforming growth factor ß1 (TGF-ß1), interleukin 10 (IL-10) and TGF-ß1 secretion, and the NF-κB signaling activity of CD4+ CD25+ Tregs were determined. Sepsis simulation with or without rSema3A increased the stability of CD4+ CD25+ Tregs, including an increase in the expression of Foxp-3, CTLA-4, and TGF-ß1, decreases in apoptosis and the methylation of foxp3-TSDR, increases in the secretion of TGF-ß1 and IL-10, and an increase in the immunosuppressive effect on CD4+ T lymphocytes. Silencing of Nrp-1 or anti-Nrp-1 treatment abrogated lipopolysaccharide (LPS) stimulation with or without an rSema3A-mediated effect. Sepsis simulation increased the DNA-binding activity of NF-κB, as well as the ratios of phosphorylated IKKß (p-IKKß) to IKKß and p-P65 to P65 in vitro and vivo Silencing of IKKß expression or PDTC treatment suppressed the stability of CD4+ CD25+ Tregs in LPS-induced sepsis. Weakening Nrp-1 reduced the stability of CD4+ CD25+ Tregs by regulating the NF-κB signaling pathway; thus, Nrp-1 could be a new target for immunoregulation in sepsis.